ENDOGENOUS NEUROPROTECTION IN GLAUCOMA

青光眼的内源性神经保护

• 批准号: 8991488
• 负责人: JEFFREY M GIDDAY
• 金额: $ 32.85万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8991488
• 关键词: Acute; Address; Affect; Age; Age-Months; American; Axon; Blindness; Brain; CCL2 gene; Cell Death; Cell Survival; Cell physiology; Cells; Chronic; Clinic; Clinical; Clinical Trials; Complex; Conditioned Reflex; Cytoprotection; Data; Diagnosis; Disease; Epigenetic Process; Experimental Models; Gene Expression; Gene Targeting; Genetic; Genetic Models; Glaucoma; Goals; Health; Human; Hypertension; Hypoxia; Hypoxia Inducible Factor; Individual; Injury; Institutes; Ischemia; Knockout Mice; Measures; Mediating; Modeling; Molecular Target; Multiple Trauma; Mus; Myocardial Ischemia; Neurodegenerative Disorders; Onset of illness; Open-Angle Glaucoma; Operative Surgical Procedures; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phototoxicity; Physical shape; Physiologic Intraocular Pressure; Physiological; Pre-Clinical Model; Primary Open Angle Glaucoma; Publications; Publishing; Regimen; Retina; Retinal; Retinal Ganglion Cells; Risk; Rodent; Running; Secondary to; Series; Staging; Stimulus; Strategic Planning; Stress; Stroke; Structure; Testing; Therapeutic; TimeLine; Wild Type Mouse; Work; base; cell injury; cellular pathology; chemokine; conditioning; disease phenotype; glaucoma test; hypoxia inducible factor 1; in vivo; mouse model; neuronal cell body; neuroprotection; novel; novel therapeutics; optic nerve disorder; pre-clinical research; preconditioning; prevent; protein expression; response; retinal ischemia; spatiotemporal; success; targeted treatment; transcription factor

 DESCRIPTION (provided by applicant): Enhancing retinal ganglion cell (RGC) survival in primary open-angle glaucoma is the fundamental treatment goal for patients with this disease, but to date, attempts to reduce intraocular pressure (IOP) secondary to surgery or drugs is the only clinically-approved approach. Primary neuroprotective therapies that directly protect RGCs from glaucomatous injury are desired, but have yet to be advanced to the clinic, largely because the complex, pan-cellular pathology that defines this disease will likely require a pleiotropic therapy capable of acting on multiple injury mechanisms concomitantly. Inducing an adaptive, multi-factorial "conditioning" response by a noninjurious stress may represent one such therapeutic approach, given its track record of demonstrated efficacy in preclinical models of retinal ischemia and phototoxicity, and the run of clinical trials of conditioning for myocardial ischemia and stroke. In fact, we recently showed that exposing mice to a series of mild systemic hypoxic stresses prior to inducing a 3-wk period of experimental glaucoma afforded robust protection of RGC soma and axons. Preliminary functional and morphologic findings provided herein document similarly robust protection even when the repetitive hypoxic stimulus is presented after disease onset. This epigenetic response to glaucoma "postconditioning" forms the basis of the present application, and our studies will be guided by the following specific aims. Specific Aim 1: Using our inducible model of experimental glaucoma, test the hypothesis that the structural and functional protection afforded RGCs by repetitive hypoxic postconditioning (HX-Post) is sustained as the disease and treatment progress. Specific Aim 2: In our inducible glaucoma model, test the related hypothesis that repetitive pharmacologic postconditioning with the clinically-approved drug deferroxamine (DFX-Post) will also afford sustained morphologic and functional protection of RGCs. The hypothesis that DFX protects RGCs via stabilization of the transcription factor hypoxia-inducible factor-1α (HIF-1α) will alsobe tested. Specific Aim 3: In the DBA/2J genetic model of glaucoma, test the hypotheses that HX-Post, and DFX-post, administered between 7.5-12.0 months of age, will positively impact 'end-stage' RGC disease phenotypes (structural and functional, somal and axonal). Specific Aim 4: Using genetic and pharmacologic approaches, test in our inducible model the hypothesis that HX-Post-mediated is critically dependent on the HIF-1α gene target CCL2 (MCP-1). Documenting sustained improvements in RGC function and structure in two distinct glaucoma models secondary to repetitive physiologic or pharmacologic postconditioning will provide strong proof-of-concept, translationally-promising evidence for the notion that a spectrum of innate epigenetics-based protective responses, some of which we will reveal here, can be activated for RGC protection in human glaucoma.

 描述（由申请人提供）：提高原发性开角型青光眼患者的视网膜神经节细胞（RGC）存活率是该疾病患者的基本治疗目标，但迄今为止，尝试通过手术或药物降低继发眼压（IOP）是唯一获得临床批准的方法。人们需要直接保护 RGC 免受青光眼损伤的初级神经保护疗法，但尚未推进到临床，这主要是因为定义这种疾病的复杂的全细胞病理学可能需要能够同时作用于多种损伤机制的多效性疗法。通过非伤害性应激诱导适应性、多因素“调节”反应可能代表了一种这样的治疗方法，因为它在视网膜缺血和光毒性的临床前模型中证明了疗效，并且进行了心肌缺血和中风调节的临床试验。事实上，我们最近表明，在诱导 3 周的实验性青光眼之前，将小鼠暴露于一系列轻度全身性缺氧应激下，可以为 RGC 胞体和轴突提供强有力的保护。本文提供的初步功能和形态学研究结果证明，即使在疾病发作后出现重复的缺氧刺激，也具有类似的强大保护作用。这种对青光眼“后处理”的表观遗传反应构成了本申请的基础，我们的研究将遵循以下具体目标。 具体目标 1：使用我们的实验性青光眼诱导模型，检验以下假设：随着疾病和治疗的进展，重复缺氧后处理 (HX-Post) 为 RGC 提供的结构和功能保护是持续的。 具体目标 2：在我们的诱导性青光眼模型中，测试相关假设，即使用临床批准的药物去铁胺 (DFX-Post) 进行重复药理学后处理也将为 RGC 提供持续的形态和功能保护。 DFX 通过稳定转录因子缺氧诱导因子-1α (HIF-1α) 来保护 RGC 的假设也将得到检验。 具体目标 3：在青光眼的 DBA/2J 遗传模型中，测试以下假设：在 7.5-12.0 个月龄之间施用 HX-Post 和 DFX-post 将对“终末期”RGC 疾病表型（结构和功能、体细胞和轴突）产生积极影响。 具体目标 4：使用遗传和药理学方法，在我们的诱导模型中测试 HX-Post 介导的假设严重依赖于 HIF-1α 基因靶标 CCL2 (MCP-1)。 记录两种不同的青光眼模型继发于重复生理或药理学后处理后 RGC 功能和结构的持续改善，将为以下观点提供强有力的概念验证和有转化前景的证据：一系列基于先天表观遗传学的保护反应（我们将在此揭示其中一些反应）可以被激活以保护人类青光眼中的 RGC。